The present invention relates to novel 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or 2-oxo-1,2,3,4-tetrahydropyrazine derivatives being useful as pharmaceuticals.
Compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton, which are compounds having one double bond in their ring, have scarcely been studied. There were only reports concerning a study of introducing a phenyl group into the 5th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives (Japanese Laid-open Patent Publication No. 275869/1990), a study of synthesis of 2-oxo-1,2,3,4-tetrahydropyrazine derivatives as synthetic intermediates of 1,5-imino-3-benzoazocine derivatives aiming at analgesics or antitussives (Japanese Laid-open Patent Publication No. 35176/1983) and the like.
Much less, there has been no report relating to a study wherein various substituents are introduced into a nitrogen atom at the 4th-position of the 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into a nitrogen atom at the 1st-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives and their pharmaceutical utility is examined. In particular, compounds having carboxy-lower alkylene converted into amide, which are subjects of the present invention, have not been studied at all.
It is a very interesting subject to synthesize novel compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton wherein various substituents are introduced into the nitrogen atom in their ring and to study their pharmaceutical utility.
The present inventors studied preparation of various novel compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton. Targets of the study are 1) to prepare novel compounds wherein carboxy-lower alkylene converted into amide is introduced into a nitrogen atom at the 4th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into a nitrogen atom at the 1st-position of 2-oxo-1,2,3,4-tetrahydropyrazine derivatives, and 2) to prepare novel compounds wherein various substituents are introduced into a nitrogen atom at the 4th-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives. As a result, the present inventors succeeded in preparing many novel compounds as mentioned later. Studying their pharmacological actions, these novel compounds were found to exhibit chymase inhibitory effects and to be useful as pharmaceuticals. The present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates in a process of the preparation of the above-mentioned 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or 2-oxo-1,2,3,4-tetrahydropyrazine derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as xe2x80x9cthe present compoundxe2x80x9d as far as there is no proviso), pharmaceutical compositions comprising them as active ingredients, and compounds represented by the general formula [II] being useful as synthetic intermediates of the present compound and salts of the intermediates (hereinafter referred to as xe2x80x9cthe present synthetic intermediatexe2x80x9d as far as there is no proviso), 
wherein
X is S or R6xe2x80x94(A2)nxe2x80x94N,
R1 and R2, being the same or different, are hydrogen, lower alkyl, cycloalkyl or aryl,
R3 and R4, being the same or different, are hydrogen, lower alkyl, cycloalkyl, aryl or aromatic heterocycles,
R5 is hydrogen, lower alkyl, cycloalkyl, aryl or xe2x80x94A3xe2x80x94A4xe2x80x94R7,
R6 is hydrogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or an aromatic heterocycle,
R7 is hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl, aryloxy, amino, lower alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle,
n is 0 or 1,
A1 is lower alkylene,
A2 is carbonyl or sulfonyl,
A3 is lower alkylene, and
A4 is carbonyl or oxalyl.
Each lower alkyl defined above can be substituted by halogen, hydroxy, lower alkoxy, aryl or aryloxy.
Each lower alkoxy defined above can be substituted by aryl.
Each lower alkylene defined above can be substituted by aryl. The same definitions are applied hereinafter. 
[wherein Q is xe2x80x94CH(OH)COxe2x80x94 or xe2x80x94CH(OH)xe2x80x94. The same definition is applied hereinafter.]
The groups defined above have the following meanings through the whole present specification.
The halogen is fluorine, chlorine, bromine or iodine.
The lower alkyl is straight-chain or branched alkyl having one to six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl. The lower alkyl can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The cycloalkyl is cycloalkyl having three to eight carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The cycloalkyl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The lower alkoxy is straight-chain or branched alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, t-butoxy or hexyloxy. The lower alkoxy can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The lower alkylene is straight-chain or branched alkylene having one to six carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, butylmethylene, isobutylmethylene, sec-butylmethylene, tert-butylmethylene, tert-butylethylene, dimethylethylene, ethylethylene, propylethylene, isopropylethylene, methyltrimethylene or propylene. The lower alkylene can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The aryl is a monocyclic or condensed aromatic hydrocarbon such as phenyl or naphthyl. The aryl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.
The aromatic heterocycle is an aromatic heterocycle having one heteroatom in the ring such as pyrrole, furan, thiophene or pyridine; an azole aromatic heterocycle such as imidazole, oxazole, thiazole, pyrazole, isoxazole or isothiazole; an aromatic heterocycle having two nitrogen atoms in the ring such as pyrazine or pyrimidine; or a condensed aromatic heterocycle such as indole, isoindole, benzimidazole, benzoxazole, benzothiazole or quinoline. Each aromatic heterocycle can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or acyl.
The nonaromatic heterocycle is a saturated nonaromatic heterocycle having one heteroatom in the ring such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran or homopiperazine; a saturated nonaromatic heterocycle having two heteroatoms in the ring such as imidazolidine, oxazolidine, thiazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine, homopiperidine or homomorpholine; an unsaturated nonaromatic heterocycle having one heteroatom in the ring such as pyrroline, dihydrofuran, dihydrothiophene, tetrahydropiperidine, dihydropiperidine, dihydropyran or pyran; or an unsaturated nonaromatic heterocycle having two heteroatoms such as imidazoline, oxazoline, thiazoline or pyrazoline. Each nonaromatic heterocycle can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or carbamoyl.
The acyl is lower alkanoyl having two to six carbon atoms such as acetyl, propionyl, butyryl, pivaloyl or pentanecarbonyl, or benzoyl. The phenyl ring of the benzoyl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.
When the present compound or the present synthetic intermediate has free hydroxy or free amino, xe2x80x94NHR (wherein R is lower alkyl) or imino, they can be protected with a general protecting group.
General protecting groups of hydroxy can be used as the protecting group of hydroxy. Specific examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl or benzoyl; alkoxycarbonyl such as lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl; substituted alkyl derivatives such as allyl, lower alkoxy-lower alkyl, substituted lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl and tetrahydrofuranyl; and substituted silyl such as lower alkylsilyl or phenylsilyl. Each phenyl ring of the above-mentioned benzoyl, phenyl-lower alkoxycarbonyl, phenyl-lower alkyl and phenylsilyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
More specific examples of the protecting group of hydroxy are acyl such as formyl, acetyl, pivaloyl, monochloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl; substituted alkyl derivatives such as allyl, methoxymethyl, 1-ethoxyethyl, 2-methoxyethoxymethyl, benzyloxymethyl, benzyl, 4-methoxybenzyl, trityl, 2-tetrahydropyranyl and 2-tetrahydrofuranyl; and substituted silyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl.
The protecting groups of amino or imino can be those which are widely used as protecting groups of amine. Specific examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl, benzoyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl or phenoxycarbonyl; substituted alkyl derivatives such as allyl, phenyl-lower alkyl and benzoyl-lower alkyl; substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl; and lower alkoxy. Each phenyl ring of the above-mentioned benzoyl, phenoxycarbonyl, phenyl-lower alkyl, benzoyl-lower alkyl and phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
More specific examples of the protecting group of amino or imino are acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or phenoxycarbonyl; substituted alkyl derivatives such as allyl, benzyl and trityl; and substituted sulfonyl such as benzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl or toluenesulfonyl.
Preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof,
(1a) X is a group selected from S and R6xe2x80x94(A2)nxe2x80x94N; and/or
(2a) R1 and R2, being the same or different, are groups selected from hydrogen, lower alkyl, cycloalkyl and aryl, wherein the lower alkyl can be substituted by a group selected from hydroxy and lower alkoxy; and/or
(3a) R3 and R4, being the same or different, are groups or rings selected from hydrogen, lower alkyl, aryl and aromatic heterocycles, wherein the aryl can be substituted by a group selected from halogen, lower alkoxy and lower alkoxycarbonyl, and the lower alkoxy can be substituted by aryl; and/or
(4a) R5 is xe2x80x94A3xe2x80x94A4xe2x80x94R7; and/or
(5a) R6 is a group or a ring selected from hydrogen, lower alkyl, cycloalkyl, lower alkoxy, aryl and aromatic heterocycles, wherein the lower alkyl can be substituted by a group selected from alkoxy, aryl and aryloxy, each lower alkoxy can be substituted by aryl, and each aryl can be substituted by a group selected from halogen, lower alkoxy and nitro; and/or
(6a) R7 is a group or a ring selected from hydrogen, lower alkyl, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, aromatic heterocycles and nonaromatic heterocycles, wherein the cycloalkyl can be substituted by lower alkyl, the lower alkyl can be substituted by halogen or hydroxy, and the nonaromatic heterocycles can be substituted by lower alkyl, cycloalkyl or aminocarbonyl; and/or
(7a) n is 1; and/or
(8a) A1 is lower alkylene, wherein the lower alkylene can be substituted by aryl; and/or
(9a) A2 is a group selected from carbonyl and sulfonyl; and/or
(10a) A3 is lower alkylene, wherein the lower alkylene can be substituted by aryl, and the aryl can be substituted by halogen; and/or
(11a) A4 is a group selected from carbonyl and oxalyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (3a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (4a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (5a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (6a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (7a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (8a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (9a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (10a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (11a) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) in the compounds represented by the general formula [I] or salts thereof.
More preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof;
(1a) X is a group selected from S and R6xe2x80x94(A2)nxe2x80x94N; and/or
(2a) R1 and R2, being the same or different, are groups selected from hydrogen and lower alkyl; and/or
(3a) R3 and R4, being the same or different, are groups selected from hydrogen and aryl, wherein the aryl can be substituted by a group selected from halogen, lower alkoxy and lower alkoxycarbonyl, and the lower alkoxy can be substituted by aryl; and/or
(4a) R5 is xe2x80x94A3xe2x80x94A4xe2x80x94R7; and/or
(5a) R6 is a group selected from lower alkyl, lower alkoxy, aryl and aromatic heterocycles, wherein the lower alkyl can be substituted by a group selected from lower alkoxy, aryl and aryloxy; and/or
(6a) R7 is a group selected from lower alkyl, lower alkoxy, aromatic heterocycles and nonaromatic heterocycles, wherein the lower alkyl can be substituted by halogen, and the nonaromatic heterocycles can be substituted by lower alkyl; and/or
(7a) n is 1; and/or
(8a) A1 is lower alkylene; and/or
(9a) A2 is a group selected from carbonyl and sulfonyl; and/or
(10a) A3 is lower alkylene, wherein the lower alkylene can be substituted by aryl; and/or
(11a) A4 is a group selected from carbonyl and oxalyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (3a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (4a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (5a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (6a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (7a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (8a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (9a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (10a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (11a) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) in the compounds represented by the general formula [I] or salts thereof.
Further preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof
(1a) X is a group selected from S and R6xe2x80x94(A2)nxe2x80x94N; and/or
(2a) R1 and R2, being the same or different, are groups selected from hydrogen and isopropyl; and/or
(3a) R3 and R4, being the same or different, are groups selected from hydrogen and phenyl; and/or
(4a) R5 is xe2x80x94A3xe2x80x94A4xe2x80x94R7; and/or
(5a) R6 is a group or a ring selected from methyl, ethyl, isopropyl, t-butyl, methoxymethyl, phenyl, phenethyl, benzyloxy and pyridine; and/or
(6a) R7 is a group or a ring selected from methyl, trifluoromethyl, heptafluoromethyl, methoxy, isopropyloxy, pyrrolidine, dihydrofuran, oxazoline, 4,4-dimethyloxazoline, thiazoline, 5,5-dimethylthiazoline, piperidine, piperazine, morpholine, oxazole, thiazole and benzothiazole; and/or
(7a) n is 1; and/or
(8a) A1 is methylene; and/or
(9a) A2 is a group selected from carbonyl and sulfonyl; and/or
(10a) A3 is phenylmethylmethylene; and/or
(11a) A4 is a group selected from carbonyl and oxalyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (3a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (4a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (5a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (6a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (7a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (8a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (9a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (10a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (11a) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) in the compounds represented by the general formula [I] or salts thereof.
The most preferred examples of the present compound are compounds wherein the group(s) is (are) the followings in the compounds represented by the general formula [I] or salts thereof,
(1a) X is a group selected from S and R6xe2x80x94(A2)nxe2x80x94N; and/or
(2a) R1 and R2, being the same or different, are groups selected from hydrogen and isopropyl; and/or
(3a) R3 and R4, being the same or different, are groups selected from hydrogen and phenyl; and/or
(4a) R5 is xe2x80x94A3xe2x80x94A4xe2x80x94R7; and/or
(5a) R6 is a group or a ring selected from methyl, phenyl and pyridine; and/or
(6a) R7 is a group or a ring selected from trifluoromethyl, isopropyloxy, oxazoline, thiazoline, 4,4-dimethyloxazoline, 5,5-dimethylthiazoline and benzothiazole; and/or
(7a) n is 1; and/or
(8a) A1 is methylene; and/or
(9a) A2 is carbonyl; and/or
(10a) A3 is phenylmethylmethylene; and/or
(11a) A4 is a group selected from carbonyl and oxalyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (2a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (3a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (4a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (5a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (6a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (7a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (8a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (9a) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (10a) in the compounds represented by the general formula [I] or salts thereof, Compounds defined by above (11a) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) in the compounds represented by the general formula [I] or salts thereof.
The salts in the present invention refer to any pharmaceutically acceptable salts and are exemplified by salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid or tartaric acid, salts with an alkaline metal or an alkaline earth metal such as sodium, potassium or calcium, quaternary salts with an organohalogen compound, and the like.
Preferred examples of the quaternary salt are quaternary salts with an alkyl halide derivative. Specific examples of the quaternary salt are quaternary salts with methyl iodide, benzyl bromide, methyl bromoacetate, 2-bromoacetamide, 2-iodoacetamide, 4-bromo-2-methyl-2-butene, farnesyl bromide, geranyl bromide or the like.
Further, some of the present compounds or the present intermediates have asymmetric carbon atoms. When there are geometric isomers or optical isomers, these isomers are also included in the scope of the present invention. The present compounds or the present intermediates can take the form of solvates such as hydrates.
The present compounds represented by the general formula [I] can be synthesized, for example, by the following typical method or according to this method. 
The above-mentioned method includes the following three synthetic routes.
Synthetic route A: compound [III]xe2x86x92compound [I]
Synthetic route B: compound [III]xe2x86x92compound [II]xe2x86x92compound [I]
Synthetic route C: compound [III]xe2x86x92compound [IV]xe2x86x92compound [V]xe2x86x92compound [VI]xe2x86x92compound [II]xe2x86x92compound [I]
These synthetic routes are specifically described hereinafter.
Synthetic Method A
The compound [III] and the amine derivative [VII] are condensed by a general method for formation of amide linkage to give the present compound [I]. Specific examples of the method are a method using a dehydrating condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1,3-dicyclohexylcarbodiimide, and a method using mixed acid anhydride such as isobutyl chloroformate.
Synthetic Method B
The compound [III] and the amine derivative [VIII] are condensed by a method similar to the synthetic method A to give the present synthetic intermediate [II]. Then, the hydroxyl group of the compound [II] is oxidized by a general oxidation method (for example, Swern oxidation method, Moffatt oxidation method, Dess-Martin oxidation method or the like) to give the present compound [I].
Synthetic Method C
The compound [III] and the amine derivative [IX] are condensed by a method similar to the synthetic method A to give the compound [IV]. Then, the hydroxyl group of the compound [IV] is oxidized by a general oxidation method (for example, Swern oxidation method, Moffatt oxidation method, Dess-Martin oxidation method or the like) to give the compound [V]. Further, the compound [V] is reacted with potassium cyanide to give the cyanohydrin derivative [VI]. Then, the compound [VI] is reacted with acetyl chloride and a lower alcohol (for example, ethanol or the like) to convert it into an iminoester derivative, and this derivative is reacted with the aminoalcohol derivative [X] to give the present synthetic intermediate [II]. Then, this intermediate is oxidized by the same oxidation method as the synthetic method B to give the present compound [I].
The amine derivatives [VII], [VIII] and [IX] to be used in these methods can be synthesized by the method described in WO 93/25574 or J. Med. Chem., 33, 2707-2714 (1990).
The above-mentioned compound [III] can be synthesized, for example, by the following typical method or similar methods. 
In the above synthetic route, X is S or R6xe2x80x94(A2)nxe2x80x94N, and Y is xe2x80x94SH, xe2x80x94NH2 or xe2x80x94NHR (wherein R is R6xe2x80x94(A2)n). Ra and Rb, being the same or different, are lower alkyl.
This synthetic route is described specifically.
The compound [XI] is reacted with the compound [XVI] under a basic condition to give the compound [XII]. (When Y is xe2x80x94NH2, the compound [XI] is reacted with the compound [XVI] and then with the acid anhydride [XVIII] or the acid chloride [XIX] to give the compound [XII].) Then, the compound [XII] is reacted with ammonia to convert it into the amide derivative [XIII], and this derivative is cyclized by refluxing it under an acidic condition to give the compound [XIV]. Then, after adding a metal hydride, the compound [XIV] is reacted with the compound [XVII] to give the compound [XV]. The ester moiety of the compound [XV] is hydrolyzed under a basic condition to give the compound [III].
The compound [III] can also be synthesized by a method described in Japanese Laid-open Patent Publication No. 35176/1983.
The compound [II] is a novel compound and a useful synthetic intermediate of the present compound [I]. In the formula, X, R1, R2, R3, R4, R7, A1 and A3 have the same definitions as in the general formula [I]. Preferred examples of the present synthetic intermediate [II] are compounds corresponding to the above-mentioned preferred examples of the present compound [I].
The compounds [I] and [II] obtained by the above-mentioned methods can be converted into the above-mentioned salts by the conventional method. As mentioned above, when there are diastereomers and optical isomers in the compounds represented by the general formulae, all these isomers are included in the present invention. When an optically active starting material is used, a single diastereomer and a single optical isomer are obtained. When a racemate is used as a starting material, respective isomers can be separated by general methods such as optical resolution methods.
As described in the section of xe2x80x9cBackground Artxe2x80x9d, compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton have scarcely been studied. 
Namely, the present compounds are novel compounds which are unknown in literatures. Features of their chemical structure composing a main skeleton are shown in the general formula [I]. The targets of the study are 1) to prepare the novel compounds wherein carboxy-lower alkylene converted into amide is introduced into the nitrogen atom at the 4th-position of the 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into the nitrogen atom at the 1st-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives, and 2) to prepare the novel compounds wherein the various substituents are introduced into the nitrogen atom at the 4th-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives.
Focusing attention on these two points and studying precisely, the present inventors have succeeded in preparing the many novel compounds.
Administration methods of drugs can be a method of administering active compounds themselves or a method of administering the drugs in the form to be decomposed in vivo and to be converted into the active compounds, namely in the form of prodrugs. Both are widely used. The present compounds have a carboxyl group in their molecule. The present compounds can be administered in the form of the carboxylic acid and also in the form of an ester which can be converted into the carboxylic acid by hydrolysis. When the present compounds have an amino group or a hydroxyl group in their molecule, the present compounds can be administered with these groups protected with suitable protecting groups.
Further, in order to find utility of the present compounds, chymase inhibitory effects of the present compounds were studied. Details will be described later in the part of xe2x80x9cPharmacological Testxe2x80x9d. The present compounds exhibited excellent chymase inhibitory effects. Chymase has been reported to exist in systemic tissues such as gut, skin and lung centering around tissues of cardiovascular system and to participate in outbreaks of physiologic functions such as cardiovascular lesion, inflammation, immune functions and tissue remodeling (Journal of Clinical and Experimental Medicine, 743 (10), 743 (1995)). Chymase has been reported to participate also in outbreaks of cardiac infarction, heart failure, blood vessel restenosis after PTCA and the like (Blood Vessel and Endothelium, 5 (5), 37 (1995)), hypertension (FEBS Lett., 406, 301(1997)), diabetes complication (Biol. Chem., Hoppe Seyler (GERMANY, WEST), 369 Suppl., p299), allergic diseases (Nobuhiko Katsunuma, xe2x80x9cIntracellular Proteolysisxe2x80x9d, p. 101-106), asthma (J. Pharmacol. Exp. Ther., 244 (1), 133 (1987)) and the like. Chymase inhibitors are expected to be effective in treating these diseases.
The present compound can be administered orally or parenterally. Examples of dosage forms are tablets, capsules, granules, powders, injections, eyedrops and the like. The present compound can be formulated into preparations by the conventional methods. For example, oral preparations such as tablets, capsules, granules and powders can be prepared by using optionally a diluent such as lactose, crystalline cellulose, starch or vegetable oil; a lubricant such as magnesium stearate or talc; a binder such as hydroxypropylcellulose or polyvinyl pyrrolidone; a disintegrator such as calcium carboxymethylcellulose or low-substituted hydroxypropylmethylcellulose; a coating agent such as hydroxypropylmethylcellulose, macrogol or silicone resin; or a film forming agent such as a gelatin film. Eyedrops can be prepared by using optionally an isotonic agent such as sodium chloride or concentrated glycerine; a buffer such as sodium phosphate or sodium acetate; a surfactant such as polyoxyethylenesorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil; a stabilizer such as sodium citrate or disodium edetate; or a preservative such as benzalkonium chloride or paraben. pH can be in a range acceptable for ophthalmic preparations, and it is more preferably in a range of 4 to 8.
The dosage of the present compound can be selected suitably depending on symptoms, age, dosage form and the like. In case of the oral preparations, the present compound can be administered once to several times per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000 mg.
Examples of preparations and formulations and results of pharmacological test of the present invention are shown below. These examples do not limit the scope of the invention, but are intended to make the invention more clearly understandable.